outcome.
Aken, M.O. van
Citation
Aken, M. O. van. (2005, March 17). Cushing's Syndrome : hormonal secretion patterns,
treatment and outcome. Retrieved from https://hdl.handle.net/1887/3748
Version:
Corrected Publisher’s Version
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Licence agreement concerning inclusion of doctoral thesis in the
Institutional Repository of the University of Leiden
Profound Amplifi c a tion of S e c re tory -B urs t M a s s a nd Anoma lous
R e g ula rity of AC T H S e c re tory Proc e s s in Pa tie nts w ith N e ls on’s
S y ndrome C ompa re d w ith C us h ing ’s D is e a s e
Maarten O. van Aken1, Alb erto M P ereira1, G errit van d en B erg 1, J o h annes A. R o m ijn1,
J o h annes D .V eld h u is 2, F erd inand R o elfs em a1
1D ep artm ent o f E nd o c rino lo g y and Metab o lic D is eas es , L eid en U nivers ity Med ic al C enter,
th e N eth erland s , and 2 E nd o c rine R es earc h U nit, D ep artm ent o f Internal Med ic ine, G eneral
C linic al R es earc h C enter, May o Med ic al S c h o o l, May o C linic and F o u nd atio n, R o c h es ter, MN 5 5 9 0 5 .
SUMMARY
Objective
As described originally, Nelson’s syndrome is characteriz ed by grossly elevated ACT H concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushing’s disease after bilateral adrenalectomy. No detailed studies have defi ned w hether the mechanisms directing ACT H secretion differ in Nelson’s syndrome and untreated Cushing’s disease.
P a tien ts a n d m eth o d s
T o address this pathophysiological issue, w e studied 9 patients fulfi lling the criteria of Nelson’s syndrome receiving glucocorticoid and mineralocorticoid replacement; 9 patients w ith untreated pituitary-dependent Cushing’s disease and 9 gender- and age-matched controls. ACT H release w as appraised by monitoring plasma ACT H concentrations in blood samples collected every 10 min for 24 h. ACT H secretion rates and endogenous decay w ere q uantifi ed by multiparameter deconvolution analysis. T he orderliness of the ACT H release process w as delineated by the approx imate entropy (ApEn) statistic. Diurnal variation in ACT H secretion w as appraised by Cosinor analysis.
R es u lts
Basal ACT H secretion w as increased 6-fold and pulsatile secretion 9-fold in patients w ith Nelson’s syndrome compared w ith Cushing’s disease (P < 0.01 and P< 0.001, respectively). T he increase in pulsatile secretion w as due to an 8-fold augmentation of burst mass. Event freq uency w as comparable in both patient groups (3 2 ± 1 vs 28 ± 2 pulses/24h), and higher than in normal controls (22 ± 1 pulses per 24 h, P< 0.0001). Paradox ically, the consistency of subordinate patterns of serial ACT H release, albeit disrupted in active Cushing’s disease, w as normal in Nelson’s syndrome (P = 0.014). Normal ACT H secretory-process regularity in Nelson’s syndrome w as attributable to a more reproducible (low er ApEn) succession of ACT H secretory-burst mass denoting more uniform amplitude evolution over 24 h (P= 0.007, Nelson vs Cushing). On the other hand, the q uantifi able regularity of serial interburst intervals (w aiting times) w as unex pectedly elevated in Nelson’s syndrome (P= 0.022). Nelson patients maintained a signifi cant diurnal rhythm in ACT H release, w hich w as marked by a 15-fold greater amplitude (P = 0.0018 vs Cushing’s) and a 4-h acrophase (max imum) delay (P= 0.03 7 vs control).
C o n clu s io n
secretory properties, concurrently required glucocorticoid replacement and/or hypothalamic injury associated with prior radiotherapy in Nelson’s syndrome.
INTRODUCTION
Nelson’s syndrome was fi rst described in 1958 as the constellation of a pituitary macroadenoma, markedly elevated ACTH concentrations, and hyperpigmentation of the skin in a patient after bilateral adrenalectomy for pituitary-dependent hypercortisolism (Cushing’s disease) (Nelson et al., 1958). The syndrome develops in 8 - 38% of adults requiring bilateral adrenalectomy for Cushing’s disease (Nagesser et al., 2000 a, K emink et al., 2001) and occurs infrequently in patients aged 40 yr or
more at the time of bilateral adrenalectomy, in contrast to patients treated at an early age (K emink et al., 1994). The pathogenetic mechanism’s underlying tumorigenesis and unrestrained ACTH secretion in Nelson’s syndrome are not well understood.
In Cushing’s disease, excessive ACTH production is characterized by a marked elevation of basal (nonpulsatile) secretion and secretory-burst mass in association with marked disruption of orderly release and diurnal rhythmicity (Van den Berg et al., 1995). Transsphenoidal adenomectomy normalises most or all alterations in ACTH secretion (Groote Veldman et al., 2000). Cushing’s disease and Nelson’s syndrome are considered to be distinct pathoaetiological presentations of the same primary biological entity. For example, impaired responsiveness to glucocorticoid enforced negative feedback on ACTH is common to both (Cook et al., 1976). In addition, under in vitro conditions the secretion of POMC-derived peptides was similar in tumoural tissue derived from patients with Cushing’s disease and Nelson’s syndrome (Westphal & Lü decke, 1984) However, CRH infusion stimulates greater and more prolonged ACTH secretion in patients with Nelson’s syndrome than Cushing’s disease (Oldfi eld et al., 1986). At present, there are relatively few other quantitative comparisons of neurosecretory control of tumoural ACTH secretion in these two clinical pathophysiological entities. The purpose of the present study was to explore and compare the 24-h spontaneous ACTH secretion dynamics in this group of patients with untreated classical Cushing’s disease and healthy controls.
Subjects and Methods
Before the availability of transsphenoidal microsurgery for the treatment of Cushing’s disease, patients usually underwent bilateral adrenalectomy. In our centre, however, patients were treated by unilateral adrenalectomy and pituitary irradiation until 1978, resulting in remission of the disease in 64% (Nagesser et al., 2000 b).
Nelson’s syndrome. We defi ned Nelson’s syndrome as bilateral adrenalectomy for Cushing’s disease in the past, plasma ACTH-levels of more than 300 ng/L during hydrocortisone replacement therapy (20 mg/day) and hyperpigmentation of the skin. Radiological evidence of a pituitary tumour was found in 7/9 patients. This defi nition of Nelson’s syndrome agrees with a previous report and discussion ( Kasperlik-Z aluska et al., 1996, Kasperlik-Kasperlik-Z aluska & Jeske, 2001). In total we studied nine patients with Nelson’s syndrome (7 females, 2 males), nine patients with proven Cushing’s disease and 9 healthy controls matched for gender and BMI.
In order to prevent spurious elevated ACTH concentrations due to low circulating cortisol concentrations under substitution, the medication was switched to dexamethasone. Therefore, starting one day before and during the sampling period, patients with Nelson’s syndrome received a standardized steroid-replacement schedule, consisting of dexamethasone 0.25 mg at 0800 and 1800 h and fl udrocortisone 0.125 mg at 0800 h.
Patients with Cushing’s disease were diagnosed by elevated 24-h urinary excretion of free cortisol, subnormal or absent suppression of plasma cortisol after administration of 1 mg dexamethasone overnight, absent or subnormal suppression of urinary cortisol excretion during a low-dose dexamethasone test, suppression of plasma cortisol by 190 nmol/L or more during a 7-h iv infusion of dexamethasone 1 mg/h (Biemond et al., 1990), positive adenoma immunostaining for ACTH and clinical cortisol dependency for several months after selective removal of the adenoma. The mean 24-h plasma cortisol concentration (mean of 145 samples of each series) was 690 ± 140 nmol/L in Cushing’s disease and 206 ± 20 nmol/L in healthy controls (P=0.008).
Table 1 Clinical characteristics of nine patients with Nelson’s syndrome
P atient S ex (m/ f)/ A g e (yr)
P rimary therapy Interv al between A D X and NS (yr)
A CTH (ng / L ) (random)*
P itu itary A denoma M edication other than adrenal steroids 1 M / 4 9 U A P I 2 8 15 0 0 not identifi ed T4 2 F / 5 7 U A P I 2 2 3 5 6 present T4 , D D A V P 3 F / 6 3 U A P I 2 5 8 8 3 present none 4 F / 5 4 U A P I 2 0 5 0 5 present none 5 F / 5 7 U A P I 2 0 6 6 8 5 present T4 6 F / 4 9 U A P I 11 3 7 2 present T4 7 F / 4 3 TS A 9 6 4 0 present none
8 M / 2 8 TS A and R T 1 10 17 present T4 , testosterone 9 F / 3 9 U A P I 2 4 10 8 3 not identifi ed none
Methods
Volunteers were admitted to the hospital on the day of the study. An indwelling iv cannula was inserted in a forearm vein at least 60 min before sampling began. Blood samples were withdrawn at 10 min intervals for 24 h, starting at 0900 h. A slow infusion of 0.9% NaCl and heparin (1 U/mL) was used to keep the line open. The subjects were free to ambulate, but not to sleep during the daytime. Meals were served at 0800, 1230 and 1730 h. Lights were turned off between 2200-2400 h. Plasma for ACTH was collected on ice in EDTA-containing tubes, centrifuged at 4o C for 10 min, and stored at – 20o C until later assays. The study was approved
by the ethical board of the Leiden University Medical Center and informed written consent was obtained from all the patients and control subjects.
A ssay s
ACTH concentrations were measured in duplicate by two-site monoclonal immunoradiometric assay (Nichol’s Institute, San Clemente, CA) with a detection limit of 2 ng/L. The intraassay coeffi cient of variation was 2.8-7.5% in the concentration range 3-300 ng/L, and 1.0-2.0 % in the concentration range of 300-1800 ng/L.
D econvolution A naly sis
Multiparameter deconvolution analysis is a technique which resolves the serum hormone concentration profi le into its constituent secretory contributions and simultaneously estimates the hormone half-life. This analysis was used to quantify underlying basal and pulsatile ACTH secretion and to estimate the corresponding (endogenous) half-life (Veldhuis et al., 1987). Daily pulsatile secretion is the product of secretory burst (pulse) frequency and the mean mass of hormone released per burst. The mass secreted per burst is the analytical integral of the secretory pulse. The latter is determined by its amplitude (maximal secretory rate) and half-duration (duration of the burst at half-maximal amplitude). Basal secretion was calculated simultaneously as time-invariant interpulse release. Secretory pulse identifi cation for ACTH required that the estimated secretory-burst amplitude exceeded zero by 95% joint statistical confi dence intervals (Veldhuis & Johnson, 1992). Based upon ACTH model simulations (Keenan et al., 2001), this statistical requirement affords 95% sensitivity and 93% specifi city of ACTH pulse detection for 10-min data (Veldhuis & Johnson, 1995).
A p p r ox imate E ntr op y ( A p E n) analy sis
model-independent quantitation of relative disorderliness, whereas higher ApEn values denote greater relative disorderliness or reduced regularity of the release process e.g., as observed for ACTH in Cushing’s disease, GH in acromegaly, and PRL in prolactinoma (Hartman et al, 1994, Groote Veldman et al.,1999,Van den Berg et al., 1997).Technically, ApEn designates the negative logarithm of the probability that a given pattern of successive hormone measurements is repeated upon next incremental comparison within a tolerance r for a data window length m. The parameter r is typically set at 20% of the individual within-series standard deviation to normalise ApEn for unequal mean serum hormone concentrations. For series of lengths < 200, m is typically given as unity. This choice of m and r yields high statistical replicability (Pincus et al., 1999). Thus ApEn is a family of statistics conditional on m and r and relatively insensitive to occasional outliers within the data and to experimental variability (noise) smaller in magnitude than r. Results are presented as absolute ApEn values and normalised ApEn ratios, defi ned by the mean ratio of absolute ApEn to that of 1000 randomly shuffl ed versions of the same series (Veldhuis & Pincus, 1998). Thus ApEn ratios of unity approach mean empirical randomness for any given sequence, whereas values less than 1.0 denote more orderly sequences. In addition, we applied ApEn to the serial interburst interval and burst-mass values from the deconvolution analysis. Thereby, we quantitate relative randomness of serial interburst interval and burst mass values (Veldhuis et al., 2001a, Farhy et al., 2002). For these measures m = 1
and r = 85% are appropriate (Pincus et al., 1999).
Nyctohemeral (24-h) rhythmicity
The twenty-four-hour variations in ACTH concentrations were analysed using a nonlinear unweighted least squares cosine approximation (cosinor analysis), as reported earlier (Veldhuis et al., 1990). Ninety-fi ve percent statistical confi dence intervals were determined for the 24-h cosine amplitude (50% of the nadir-zenith difference), mesor (rhythmic mean) and acrophase (clock-time of maximal value).
Statistical analysis
RESULTS
ACTH secretion
Figure 1 illustrates representative profi les of 24 h plasma ACTH concentrations over time in patients with Nelson’s syndrome, Cushing’s disease and controls. Deconvolution analysis was used to quantify specifi c secretory and kinetic features of ACTH output: Table 2. In patients with Nelson’s syndrome, basal ACTH production was increased 6-fold and pulsatile secretion 9-fold compared with values in Cushing’s patients. The increase in pulsatile secretion was attributable to an 8-fold increased mass of ACTH released per event (583 ± 160 ng/L vs 75 ± 20 ng/L, P < 0.001) (fi gure 2), and the 12-fold increased amplitude (maximal rate of secretion, P<0.0001). In contrast, event frequency (32.3 ± 1 vs 28.3 ± 2, P = 0.1) and the apparent half-life of ACTH (18.8 ± 1.4 vs 17.8 ± 2.0 min, P = 0.51) were comparable to estimates in Cushing’s disease. Neither state of ACTH excess was associated with any change in ACTH half-life. The results of the deconvolution analysis of the controls are listed in Table 2.
Table 2 Multiparameter deconvolution of the 24 h ACTH plasma profi les in patients with Nelson’s syndrome, untreated patients with Cushing’s disease and healthy controls
Nels o n Cu s hin g Co n tro ls P - v alu e Basal secretion rate (ng/L/min) 13.36±7.0 b 2.10±0.49 0.2043±0.0435e < 0.001
Pulse half duration (min) 24.2±2.1 33.5±3.8 18.9±3.0 0.002 Pulse frequency 32.3±1.0 28.3±2.0 21.9±1.1e < 0.001
Half-life (min) 18.8±1.4 17.8±2.0 20.5±1.4 0.47 Mean pulse interval (min) 44.6±1.7a 52.6±3.0 65.9±2.7e 0.002
Mean pulse secretory mass (ng/L) 583±160c 75.0±19.7 21.1±3.2e < 0.0001
Mean pulse secretory rate (ng/L/min) 24.2±7.25d 2.06±0.34 1.09±0.12e < 0.0001
24-h basal secretion (ng/L) 19230±10130b 3030±710 290±60e < 0.001
24-h pulsatile secretion (ng/L) 18240±4470c 2000±450 470±90e < 0.0001
Total secretion/24h (ng/L) 37470±11980c 5030±970 760±120e < 0.0001
Data were analysed by the K ruskal-W allis test (last column). Differences between groups were evaluated by the Mann-W hitney test. Statistical differences between the Nelson and Cushing groups are shown as a: P< 0.05, b: P< 0.01, c: P< 0.001, d < 0.0001. Statistical differences between Nelson and control groups are given as: e: P< 0.001. Data are shown as mean ± SE M.
ACTH nyctohemeral variation
Nelson 0 200 400 600 800 1000 1200 1400 1600 A C T H ( n g /L ) 0 400 800 1200 1600 2000 2400 2800 0 200 400 600 800 1000 1200 1400 1600 A C T H S ec re ti o n R at e (n g /L /m in ) 0 50 100 150 200 250 300
Control subject
Time (min) 0 200 400 600 800 1000 1200 1400 1600 A C T H ( n g /L ) 0 10 20 30 40 50 60 0 200 400 600 800 1000 1200 1400 1600 A C T H S ec re ti o n R at e (n g /L /m in ) 0 1 2 3 4 Cushing 0 200 400 600 800 1000 1200 1400 1600 A C T H ( n g /L ) 0 20 40 60 80 100 120 0 200 400 600 800 1000 1200 1400 1600 A C T H S ec re ti o n R at e( n g /L /m in ) 0 2 4 6 8 10
n g /L /m in 0.01 0.1 1 10 100
Basal Secretion Rate
n g /L 1 10 100 1000 10000 Burst M ass
Nelson Cushing Control Nelson Cushing Control
P < 0.01 P < 0.001
Figure 2. Scatter plots of the basal ACTH secretion rate and ACTH burst mass, calculated by multiparameter deconvolution in 9 patients with Nelson’s syndrome and in the same number of patients with Cushing’s disease (pituitary dependent hypercortisolism) and age-and gender-matched controls. The signifi cance level is shown for the Kruskal-Wallis test. Note that the data are shown on a logarithmic scale.
0.2 0.4 0.6 0.8 1.0 1.2 0.2 0.4 0.6 0.8 1.0 1.2
Serial Burst M ass ApEn Serial Burst Interval ApEn
Controls Cushing Controls
Cushing Nelson
Nelson
P=0.04 P=0.03
Approximate Entropy
ApEn analysis was applied to the 24-h ACTH concentration profi les to quantitate the regularity of the release process: Table 4. ApEn of ACTH release in Nelson’s syndrome did not differ from that in controls, but was signifi cantly elevated in patients with Cushing’s disease, as reported earlier. The latter denotes the highly irregular minute-to-minute ACTH release. To investigate the (unexpected) preservation of pattern regularity of ACTH release in patients with Nelson’s syndrome, ApEn analysis was also applied to the succession (ordered series) of calculated ACTH burst-mass and interburst-interval values. Statistical comparisons revealed that ApEn of serial interburst intervals was lower in Nelson patients than in controls, indicating heightened regularity of tumour secretory event timing (fi gure 3). In addition, ApEn estimates of sequential ACTH burst mass in Nelson patients was lower than that in Cushing’s patients, but similar to that in controls.
Table 3 Cosinor analysis of the 24 h plasma ACTH concentration series
Nelson M. Cushing Normal Controls P-value Mesor (ng/L) 1 750 ± 350 a 75 ± 14 12.7 ± 1.4 c <0.001
Amplitude (ng/L) 2 160 ± 70 b 10.8 ± 2.1 5.1 ± 0.7 c 0.004
Acrophase (clock hour ± min) 3 1210 ± 113 1618 ± 132 0754 ± 20 d <0.001
Data were analysed by the Kruskal-Wallis test (last column). Differences between groups were evaluated with the Mann-Whitney test. Differences between the Nelson and Cushing groups are shown as a: P= 0.0012, b: P= 0.0018. Statistical signifi cant differences between Nelson and control groups are given as: c: P= 0.0005, d: P= 0.037. Data are shown as mean ± SEM. 1:mean value about which the 24-h rhythm varies. 2: 50% of the
nadir-to-zenith difference in ACTH concentration. 3: time of maximum value.
Table 4 Approximate Entropy analyses of the relative orderliness of ACTH secretion in patients with Nelson’s syndrome, Cushing’s disease and healthy controls
Nelson’s syndrome
Cushing Control P value Nelson vs Cushing
P value Nelson vs Control ApEn (ACTH) 1.018 ± 0.133 1.420 ± 0.061 0.902 ± 0.049 0.014 0.42 ApEn ratio (ACTH) 0.576 ± 0.069 0.754 ± 0.029 0.507 ± 0.030 0.031 0.37 Serial burst interval (ACTH) 0.797 ± 0.065 0.880 ± 0.047 0.998 ± 0.040 0.34 0.022 Serial burst mass (ACTH) 0.769 ± 0.061 0.974 ± 0.026 0.807 ± 0.066 0.007 0.67
DISCUSSION
Albeit not established previously to our knowledge, an expected and striking feature in patients with Nelson’s syndrome is the multifold elevation of both basal (time-invariant) and pulsatile (episodic) ACTH secretion. This prediction arises from the combined amplifi cation of basal and pulsatile hormonal release by GH- and prolactin-secreting pituitary tumours (Hartman et al., 1994; Groote Veldman et al., 1999). In contrast, we are unaware of any precedence for (paradoxically) accentuated regularity of adenomatous hormone secretion. Indeed, a cardinal property of neuroendocrine neoplasms is marked deterioration of the quantitative consistency of the release process. Accordingly, the present analytical platform establishes joint secretory mechanisms driving elevated mean plasma ACTH concentrations and unique neuroregulatory contrasts in Nelson’s syndrome and Cushing’s disease.
Two hallmarks of Cushing’s disease are diminished suppressibility of ACTH secretion to glucocorticoids and blunted diurnal rhythmicity. These abnormalities are accompanied by increased basal and pulsatile secretion of ACTH and cortisol and marked deterioration of the individual and joint regularity of the release of both hormones (Van den Berg et al., 1995; Roelfsema et al., 1998). The present data in Nelson’s syndrome identify some similitude with more extensively studied Cushing’s disease; viz ., elevated ACTH secretory-burst frequency, amplitude (mass) and basal release.; delayed timing of the daily maximum in ACTH secretion; and normal ACTH elimination half-life.
In as much as Nelson’s syndrome occurs primarily in patients with Cushing’s disease after bilateral adrenalectomy a plausible (but unproven) exacerbating factor is therapeutically incomplete restoration of physiological negative feedback by cortisol or synthetic congeners. In this regard, acute metyrapone administration to healthy individuals induces a 12-fold amplifi cation of ACTH secretory burst mass along with a lesser elevation in basal (non-pulsatile) secretion (1.5-fold) and pulse frequency (1.4-fold) (Veldhuis et al., 2001b). However, 60-fold higher basal
cells may heighten this marker of unregulated release. The latter concept has been verifi ed in hyperparathyroidism associated with longstanding renal failure (Schmitt et al., 1998).
Our patients were studied while using a standardized steroid-replacement schedule, consisting of dexamethasone 0.25 mg at 0800 and 1800 h and fl udrocortisone 0.125 mg at 0800 h. This schedule was used to obtain stable and approximately physiological systemic glucocorticoid availability. In this regard, Cook et al. (1976) reported that a daily dose of 2 mg dexamethasone does not suppress plasma ACTH concentrations in patients with Nelson’s syndrome, while completely suppressing ACTH secretion in patients with congenital adrenal hyperplasia. Nonetheless, the current data do not explore the potential impact of varying dexamethasone doses on ACTH dynamics. In the latter regard, one patient (of four) with Nelson’s syndrome studied by Karl and colleagues exhibited a mutant glucocorticoid receptor, thereby putatively muting glucocorticoid negative feedback (Karl et al., 1996).
Apparent pulse frequency was elevated comparably in Nelson’s syndrome and Cushing’s disease, as inferred also in patients with somatotropinomas and prolactinomas (Hartman et al., 1994; Groote Veldman et al., 1999). The basis for this general fi nding is not established. However, curative pituitary adenomectomy typically normalizes this feature (Groote Veldman et al., 2000; van den Berg et al., 1994). The latter data could indicate that accelerated event frequency refl ects autonomous properties of adenomatous cells, abnormal tumoural-product feedback on hypothalamic centers, and/or technical overestimation of diminutive release episodes as d e fac to pulses. Heightened irregularity of tumoural hormone release is an established statistical marker of reduced feedback responsivity (Hartman et al., 1994; Veldhuis et al., 2001c), and would concomitantly accentuate the analytical
risk of type I (false positive) pulse enumeration (Veldhuis & Johnson, 1995). A signifi cant delay in diurnal timing of the ACTH concentration maximum of the 24-h rhythm points toward partial hypothalamic supervision of adenomatous secretion. Although the former shift in ACTH acrophase is not observed in patients with CAH withdrawn from glucocorticoid replacement (unpublished), acute blockade of cortisol synthesis does induce 3-h acrophase delay in healthy adults (Veldhuis et al., 2001b). Acromegaly and tumoural or functional hyperprolactinaemia
appear to differ in this regard. In these disorders either no shift in acrophase or only a modest shift is found. In prolactinomas, but also in functional hypothalamic disconnection, no change in acrophase is present, where in active acromegaly an advance shift of about 3 h was observed (Groote Veldman et al., 1999; van den Berg et al., 1994). These divergent observations do not allow ready generalizations at present.
control was specifi c to ACTH, since GH output was equivalently irregular in the two hypercorticotropinaemic states (data not shown). Acute reduction in cortisol feedback in healthy adults also signifi cantly increases ACTH orderliness (Veldhuis et al., 2001b). Signifi cantly enhanced ACTH regularity in Nelson’s syndrome
compared with Cushing’s disease could therefore refl ect greater resistance to glucocorticoid negative feedback in the former case. In addition, secretagogue infusion studies and simpler reductionist mathematical models predict that reduced feedforward signalling can maintain more regular system output (Veldhuis et al., 2001). According to this analytical framework, lesser endogenous CRH and/or AVP drive (for instance as caused by pituitary irradiation), could facilitate more orderly ACTH secretion in Nelson’s syndrome than in Cushing’s disease. Lastly, the higher ACTH concentrations cannot explain this unique distinction, since the statistically normalized ApEn statistic adjusts analytically for markedly unequal mean hormone measurements (Pincus, 1991; Hartman et al., 1994; Pincus, 1994). In addition, ApEn analyses of sequences of (deconvolved) ACTH secretory-burst mass and interburst-interval times corroborate a paradoxical increase in orderliness in patients with Nelson’s syndrome.
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